Search

Primary ciliary dyskinesia (PCD) is a rare, inherited disease characterized by impaired motile ciliary function leading to chronic sinopulmonary disease, persistent middle ear effusions, laterality defects, and subfertility. Over fifty PCD-associated genes have also been identified, which have provided new insights into the processes involved into ciliary assembly, structure, and function. Historically, the diagnosis of PCD was based on the presence of ultrastructural defects in the ciliary axoneme but with identification of a growing number of disease-associated genes, genetic testing has become a first-line diagnostic tool. Other approaches have also evolved, that have improved our diagnostic capabilities. Treatments for PCD have lagged, and though our growing understanding of the genetic and pathophysiological bases of the disease of PCD may yield to better therapeutic strategies., (© 2024 Wiley Periodicals LLC.)

Electronic cigarettes are driving a new epidemic of nicotine dependence among youths and are now the dominant tobacco product used by adolescents in the United States and other countries. Candy and fruit flavorings have driven their use, and many products contain higher nicotine concentrations, which contributed to their addictive potential. Numerous epidemiologic studies have described increased rates of respiratory symptoms in adolescent electronic cigarette users, and in vitro and in vivo studies showed that electronic cigarette vapors exert extensive biological effects on human airways, different from tobacco smoke, leading to epithelial cell dysregulation, inflammation, mucus hypersecretion, and apoptosis. Severe acute lung injury has been reported in adolescents and young adults, particularly in those using tetrahydrocannabinol (THC)-containing products, underscoring the threats of electronic cigarettes to lung health., (© 2024 Wiley Periodicals LLC.)

Background: With more than 103 million cases and 1.1 million deaths, the COVID-19 pandemic has had devastating consequences for the health system and the well-being of the entire US population. The Rare Diseases Clinical Research Network funded by the National Institutes of Health was strategically positioned to study the impact of the pandemic on the large, vulnerable population of people living with rare diseases (RDs)., Objective: This study was designed to describe the characteristics of COVID-19 in the RD population, determine whether patient subgroups experienced increased occurrence or severity of infection and whether the pandemic changed RD symptoms and treatment, and understand the broader impact on respondents and their families., Methods: US residents who had an RD and were <90 years old completed a web-based survey investigating self-reported COVID-19 infection, pandemic-related changes in RD symptoms and medications, access to care, and psychological impact on self and family. We estimated the incidence of self-reported COVID-19 and compared it with that in the US population; evaluated the frequency of COVID-19 symptoms according to self-reported infection; assessed infection duration, complications and need for hospitalization; assessed the influence of the COVID-19 pandemic on RD symptoms and treatment, and whether the pandemic influenced access to care, special food and nutrition, or demand for professional psychological assistance., Results: Between May 2, 2020, and December 15, 2020, in total, 3413 individuals completed the survey. Most were female (2212/3413, 64.81%), White (3038/3413, 89.01%), and aged ≥25 years (2646/3413, 77.53%). Overall, 80.6% (2751/3413) did not acquire COVID-19, 2.08% (71/3413) acquired it, and 16.58% (566/3413) did not know. Self-reported cases represented an annual incidence rate of 2.2% (95% CI 1.7%-2.8%). COVID-19 cases were more than twice the expected (71 vs 30.3; P<.001). COVID-19 was associated with specific symptoms (loss of taste: odds ratio [OR] 38.9, 95% CI 22.4-67.6, loss of smell: OR 30.6, 95% CI 17.7-53.1) and multiple symptoms (>9 symptoms vs none: OR 82.5, 95% CI 29-234 and 5-9: OR 44.8, 95% CI 18.7-107). Median symptom duration was 16 (IQR 9-30) days. Hospitalization (7/71, 10%) and ventilator support (4/71, 6%) were uncommon. Respondents who acquired COVID-19 reported increased occurrence and severity of RD symptoms and use or dosage of select medications; those who did not acquire COVID-19 reported decreased occurrence and severity of RD symptoms and use of medications; those who did not know had an intermediate pattern. The pandemic made it difficult to access care, receive treatment, get hospitalized, and caused mood changes for respondents and their families., Conclusions: Self-reported COVID-19 was more frequent than expected and was associated with increased prevalence and severity of RD symptoms and greater use of medications. The pandemic negatively affected access to care and caused mood changes in the respondents and family members. Continued surveillance is necessary., (©Maurizio Macaluso, Marc E Rothenberg, Thomas Ferkol, Pierce Kuhnell, Henry J Kaminski, David W Kimberlin, Michael Benatar, Mirna Chehade, The Principal Investigators of the Rare Diseases Clinical Research Network – Cycle 4. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 14.02.2024.)

Nasal nitric oxide (nNO) is extremely low in most people with primary ciliary dyskinesia (PCD) and its measurement is an important contributor to making the diagnosis. Existing guidelines and technical standards focus on nNO measurements in older, cooperative children using chemiluminescence analysers. However, measurements of nNO in pre-school-age children (age 2-5 years) may facilitate early diagnosis and electrochemical rather than chemiluminescence analysers are widely used. Pre-schoolers often need different methods to be employed when measuring nNO. Hence, a European Respiratory Society Task Force has developed this technical standard as the first step towards standardising sampling, analysis and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups, including pre-school-age children. Furthermore, we considered both chemiluminescence and electrochemical analysers that are in use worldwide. There was a paucity of quality evidence for electrochemical analysers and sampling methods used in young children, and the Task Force proposes future research priorities to allow updates of this technical standard., Competing Interests: Conflict of interest: N. Beydon reports educational writing payments as a member of the HERMES examination committee for paediatric respiratory medicine of the European Respiratory Society, and a leadership role as Chair of Group 07.01 of the European Respiratory Society (Paediatric respiratory physiology and sleep), outside the submitted work. P. Latzin reports grants from Vertex and OM Pharma, lecture honoraria from Vertex, Vifor and OM Pharma, and advisory board participation from Polyphor, Santhera (DMC), Vertex, Vifor, OM Pharma and Sanofi Aventis, outside the submitted work. S.D. Davis reports grants from the National Institutes of Health/National Heart, Lung, and Blood Institute, to support the present manuscript, and consulting fees from Parion Sciences and ReCode Therapeutics, and advisory board participation for the PCD Foundation, outside the submitted work. T. Ferkol reports grants from the National Institutes of Health (HL096458) to support the present manuscript, and grants from the National Institutes of Health (HL116211, HL125241, AI146999), National Health and Medical Research Council (NHMRC1043768) and Parion Sciences, advisory board participation for the PCD Foundation, Parion Sciences and Translate Bio, and is past president and executive board member of the American Thoracic Society, outside the submitted work. J.S. Lucas reports grants from AAIR Charity and NIHR Research for patient benefit, and consulting fees from Translate Bio, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Nasal nitric oxide (nNO) measurements are used in the assessment of patients suspected of having primary ciliary dyskinesia (PCD), but recommendations for performing such measurements have not focused on children and do not include all current practices. To guide the development of a European Respiratory Society-supported technical standard for nNO measurement in children, an international online survey was conducted to better understand current measurement practices among providers involved in PCD diagnostics. 78 professionals responded, representing 65 centres across 18 countries, mainly in Europe and North America. Nearly all centres measured nNO in children and more than half performed measurements before 5 years of age. The test was often postponed in children with signs of acute airway infection. In Europe, the electrochemical technique was more frequently used than chemiluminescence. A similar proportion of centres performed measurements during exhalation against a resistance (49 out of 65) or during tidal breathing (50 out of 65); 15 centres used only exhalation against a resistance and 15 used only tidal breathing. The cut-off values used to discriminate PCD were consistent across centres using chemiluminescence analysers; these centres reported results as an output (nL·min -1 ). Cut-off values were highly variable across centres using electrochemical devices, and nNO concentrations were typically reported as ppb. This survey is the first to determine real-world use of nNO measurements globally and revealed remarkable variability in methodology, equipment and interpretation. These findings will help standardise methods and training., Competing Interests: Conflict of interest: N. Beydon declares no competing interests. Conflict of interest: T. Ferkol declares no competing interests. Conflict of interest: A.L. Harris declares no competing interests. Conflict of interest: M. Colas declares no competing interests. Conflict of interest: S.D. Davis declares grant NIH U54 HL09640958 funded by the Office of Rare Diseases Research (NCATS) in the 36 months prior to manuscript submission, and membership of the PCD Foundation Medical and Scientific Advisory Council. Conflict of interest: E. Haarman declares no competing interests. Conflict of interest: C. Hogg declares no competing interests. Conflict of interest: E. Kilbride declares no competing interests. Conflict of interest: P. Kouis declares no competing interests. Conflict of interest: C.E. Kuehni declares no competing interests. Conflict of interest: P. Latzin declares grants to their institution from Vertex and Vifor; payment to their institution and themself for lectures, presentations, speaker bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma; and paid (to their institution and/or themself) participation on data safety monitoring or advisory boards for Polyphor, Santhera (DMC), Vertex, OM Pharma, Vifor and Sanofi Aventis, all in the 36 months prior to manuscript submission. Conflict of interest: D. Marangu declares no competing interests. Conflict of interest: J. Marthin declares no competing interests. Conflict of interest: K.G. Nielsen declares no competing interests. Conflict of interest: P. Robinson declares no competing interests. Conflict of interest: N. Rumman declares no competing interests. Conflict of interest: M. Rutter declares no competing interests. Conflict of interest: W. Walker declares no competing interests. Conflict of interest: J.S. Lucas declares no competing interests., (Copyright ©The authors 2022.)

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disease arising from motile ciliary dysfunction and associated with recurrent and chronic upper and lower respiratory tract infections. Pediatric otolaryngologists may see these patients prior to the development of lung disease. Features of PCD may overlap with other suppurative respiratory diseases, creating diagnostic challenges. A simple screening tool would be beneficial to identify potential patients who have chronic upper respiratory tract disease requiring further specialist evaluation., Objective: To test a simple screening tool consisting of four questions to detect PCD in children with chronic otitis media and chronic rhinosinusitis seen in a tertiary otolaryngology clinic., Methods: A prospective, single site, observational study in a tertiary care pediatric otolaryngology clinic. Children aged 3-17 years diagnosed with chronic otitis media or rhinosinusitis with onset at less than 2 years of age were recruited. All study subjects had at least one of four key clinical features for PCD as determined by answers to screening questions, while control subjects had none. All participants completed a medical history questionnaire and nasal nitric oxide measurements. Those with reduced nasal nitric oxide levels were referred to our PCD center for further evaluation., Results: A total of 153 patients were screened and 62 subjects were enrolled. Of those, 35 were enrolled as study subjects and 27 as matched controls. Study subjects had mean age of 7.5 years (3.2-16.5) with pre-screening diagnosis of chronic otitis media (n = 29) or chronic rhinosinusitis (n = 6). Control subjects (n = 27) had mean age 7.2 years (3.0-16.3) with pre-screening diagnosis of chronic otitis media (n = 25), and chronic rhinosinusitis (n = 2). There were no differences in subject demographics or mean nasal nitric oxide values between the two groups (179.8 vs 210.8 nl/min). Ten individuals had low nasal nitric oxide values, 7 of which were normal on repeat testing. Three subjects failed to return for follow up evaluations. Four referrals were made for further evaluation on the basis of clinical symptoms and nasal nitric oxide results. While no new cases of PCD were detected, a subject and his sibling with recurrent sinopulmonary infections were referred for immunologic evaluation., Conclusion: The use of standardized screening questions can be used in an otolaryngology clinic to identify patients who require further evaluation for PCD or primary immunodeficiency., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tobacco has long been known to be one of the greatest causes of morbidity and mortality in the adults, but the effects on the foetus and young children, which are lifelong, have been less well appreciated. Developing from this are electronic nicotine delivery systems or vapes, promulgated as being less harmful than tobacco. Nicotine itself is toxic to the foetus, with permanent effects on lung structure and function. Most vapes contain nicotine, but they also contain many other compounds which are inhaled and for which there are no toxicity studies. They also contain known toxic substances, whose use is banned by European Union legislation. Accelerating numbers of young people are vaping, and this does not reflect an exchange of vapes for cigarettes. The acute toxicity of e-cigarettes is greater than that of tobacco, and includes acute lung injury, pulmonary haemorrhage and eosinophilic and lipoid pneumonia. Given the worse acute toxicity, it should be impossible to be complacent about medium and long term effects of vaping. Laboratory studies have demonstrated changes in lung proteomics and the innate immune system with vaping, some but not all of which overlap with tobacco. It would be wrong to consider vapes as a weaker form of tobacco, they have their own toxicity. Children and young people are being targeted by the vaping industry (which is largely the same as the tobacco industry), including on-line, and unless an efficient legislative program is put in place, a whole new generation of nicotine addicts will result., (Copyright © 2021 Andrew Bush, Thomas Ferkol, Algirdas Valiulis, Artur Mazur, Ivane Chkhaidze, Tamaz Maglakelidze, Sergey Sargsyan, Gevorg Boyajyan, Olga Cirstea, Svitlana Doan, Oleksandr Katilov, Valeriy Pokhylko, Leonid Dubey, Edita Poluziorovienė, Nina Prokopčiuk, Vaida Taminskienė, Arūnas Valiulis.)

Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Biallelic deleterious variants in RTTN, which encodes rotatin, are associated with primary microcephaly, polymicrogyria, seizures, intellectual disability, and primordial dwarfism in human infants., Methods and Results: We performed exome sequencing of an infant with primary microcephaly, pontocerebellar hypoplasia, and intractable seizures and his healthy, unrelated parents. We cultured the infant's fibroblasts to determine primary ciliary phenotype., Results: We identified biallelic variants in RTTN in the affected infant: a novel missense variant and a rare, intronic variant that results in aberrant transcript splicing. Cultured fibroblasts from the infant demonstrated reduced length and number of primary cilia., Conclusion: Biallelic variants in RTTN cause primary microcephaly in infants. Functional characterization of primary cilia length and number can be used to determine pathogenicity of RTTN variants.

Chronic respiratory disease can affect growth and nutrition, which can influence lung function. We investigated height, body mass index (BMI), and lung function in patients with primary ciliary dyskinesia (PCD).In this study, based on the international PCD (iPCD) Cohort, we calculated z-scores for height and BMI using World Health Organization (WHO) and national growth references, and assessed associations with age, sex, country, diagnostic certainty, age at diagnosis, organ laterality and lung function in multilevel regression models that accounted for repeated measurements.We analysed 6402 measurements from 1609 iPCD Cohort patients. Height was reduced compared to WHO (z-score -0.12, 95% CI -0.17 to -0.06) and national references (z-score -0.27, 95% CI -0.33 to -0.21) in male and female patients in all age groups, with variation between countries. Height and BMI were higher in patients diagnosed earlier in life (p=0.026 and p<0.001, respectively) and closely associated with forced expiratory volume in 1 s and forced vital capacity z-scores (p<0.001).Our study indicates that both growth and nutrition are affected adversely in PCD patients from early life and are both strongly associated with lung function. If supported by longitudinal studies, these findings suggest that early diagnosis with multidisciplinary management and nutritional advice could improve growth and delay disease progression and lung function impairment in PCD., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)